Malignant melanoma is responsible for 79% of skin cancer-related death, despite the fact that it accounts for only 4% of all skin cancers[1]. Australia and New Zealand have the highest rate of incidence and mortality for melanoma and its occurrence is reported to be on the rise [2].
Malignant melanoma arises from mutations in the melanin producing cells, melanocytes. Because melanocytes are found mostly in the epidermal layer of the skin, it is consequently the most common place for primary melanoma lesions [3]. Primary lesions can also occur at non-cutaneous sites where melanocytes are found, such as the oral mucosa, nasopharynx, paranasal sinuses, tracheobronchial tree, vulva, vagina, anus, urinary tract, central nervous system and eye [4]. A staging system is used to measure the extent and seriousness of the disease that is based on the examination of the primary tumour and the extent of the spread. Because no reliable blood markers have been identified for screening purposes, diagnosis relies on measurements obtained through physical examination and radiology techniques. These measurements are used to determine overall staging (Stage 0 to Stage IV) and patient prognosis. Early stages (0, I and II) show no spread of the primary tumour and have very good prognosis. These early stages are differentiated mainly based on depth of the invading tumour. When the primary tumour has metastasised to the lymph glands or surrounding tissue but not to a distant lymph node or other organ, the patient is diagnosed as stage III. When the melanoma has spread to a distant organ(s) or distant lymph gland(s), stage IV of the disease is diagnosed [5]. Since early stages of melanoma are generally symptomless, by the time a patient is diagnosed the cancer is generally at advanced stages (stages III or IV) and prognosis is consequently poor.
Early detection of cutaneous melanoma followed by an appropriate intervention has the most impact on the prognosis of patients with melanoma. When detected at stages 0-II, the recommended treatment is to remove the primary tumour, the skin and the flesh from around the primary tumour through surgery. When the condition is recognised early in its course and the primary tumour is surgically removed 97% of patients show no recurrence of the problem. Because incompletely excised tumours have a high rate of recurrence, and since patients with recurrent lesions have lower rates of long term cure, it is important to remove the entire tumour [6]. The depth of invasion of the tumor at the time of diagnosis most accurately predicts survival from melanoma: the survival rate associated with melanoma is inversely related to its depth at the time of diagnosis. When the primary melanoma has invaded more deeply, a sentinel node biopsy is conducted for more accurate staging of the disease and to assist in determining the need for additional treatment.
When later stages (III and IV) are diagnosed, the treatment options that exist for malignant melanoma are unsatisfactory, and long term survival of metastatic melanoma patients is a relatively rare event [7]. For stage III patients, the lymph node surrounding the node that tested positive to melanoma is generally removed. When patients are medically unfit for surgery or have unresectable disease because it is too extensive, radiotherapy may be used as an alternative to surgery. Post-operative radiotherapy is also considered in patients who have positive or close margins following surgery or where metastases to lymph nodes raise the risk of regional occurrence [8]. For stage IV melanoma, the standard treatment is chemotherapy using dacarbazine (DTIC) [9]. Other chemotherapy drugs such as lomustine and fotemustine are also approved for stage IV melanoma [10].
Two biological therapies have received FDA approval for use in the treatment of high risk melanoma patients: interferon alpha-2b and IL-2. Interferon alpha-2b is prescribed as adjuvant therapy to alter the natural history of the disease and in some studies shown to decrease recurrence rates of patients with fully resected high-risk malignant melanoma [11]. The treatment, however, requires repeated administration over a 52 week period which is associated with significant toxicities and considerable cost [12]. IL-2 is an immunotherapeutic agent used for patients with metastatic melanoma and is associated with a low but consistent rate of overall response of ˜13-17% (7-% partial response and 6-8% complete response) [13, 14].
Melanoma is an immunogenic cancer. Large numbers of tumour infiltrating lymphocytes are often found naturally in melanoma patients, and many studies have reported that melanoma cells express antigens that can induce melanoma-specific T cell and antibody responses [15]. This has led to the design of various melanoma vaccine strategies, some of which are composed of whole cells, cell lysates, proteins and others of specific peptides. Dendritic cell-based vaccines that use ex vivo antigen-loaded DCs have also been tested with the aim of enhancing the patient's immune response to the tumour. However, despite over 15 years of studies none have yet been approved for use outside of a clinical trial [16].
Accordingly, there remains a need for an effective melanoma treatment.